Modafinil (C15H15NO2S), is 2-(benzhydryl-sulfinyl)acetamide, and is also known as 2-[(diphenylmethyl) sulfinyl] acetamide.
Modafinil has been described as presenting a “neuropsychopharmacological spectrum characterized by the presence of excitation with hyperactivity and of hypermotility; and by the absence of stereotypy (except in high doses) and of potentialization of the effects of apomorphine and amphetamine” (U.S. Pat. No. 4,177,290; hereinafter the “'290 patent,” which is incorporated in its entirety herein by reference). A single administration of modafinil results in increased locomotor activity in mice and increased nocturnal activity in monkeys. Duteil et al., Eur. J. Pharmacol., 1990, 180, 49. Modafinil has been successfully tested in humans for treatment of idiopathic hypersomnia and narcolepsy. Bastuji et al., Prog. Neuro-Psych. Biol. Psych., 1988, 12, 695.
Other uses of modafinil have been presented. U.S. Pat. No. 5,180,745, incorporated in its entirety herein by reference, discloses the use of modafinil for providing a neuroprotective effect in humans, and in particular for the treatment of Parkinson's disease. The levorotatory form of modafinil, i.e.,(-)benzhydrylsulfinyl-acetamide, may have potential benefit for treatment of depression, hypersomnia and Alzheimer's disease (U.S. Pat. No. 4,927,855, incorporated in its entirety herein by reference). European Published Application 547952 (published Jun. 23, 1993) discloses the use of modafinil as an anti-ischemic agent. European Published Application 594507 (published Apr. 27, 1994) discloses the use of modafinil to treat urinary incontinence.
Preparations of modafinil having a defined solid particle size have been described in U.S. Pat. No. 5,618,845, incorporated in its entirety herein by reference, and preparations of a levorotatory isomer of modafinil was described in U.S. Pat. No. 4,927,855. Heterocyclic derivatives of modafinil are disclosed in U.S. patent application Ser. No. 60/204,789, incorporated in its entirety herein by reference.
Modafinil has been approved for use in humans in 100 mg and 200 mg solid unit dose forms in the U.S. It is also desirable to formulate modafinil in liquid compositions. However, formulation of modafinil in liquid compositions is hampered by the low solubility and unpleasant taste of the modafinil compound. It is desirable to formulate compositions that effectively taste-mask the modafinil compound and provide a therapeutically effective amount of the same. It has been found that use of a complexing agent can achieve these goals, thereby enhancing the pharmacological properties of compositions of modafinil compound. The use of cyclodextrins allow for the formulation of a modafinil compound in aqueous solutions suitable for oral administration, and provide for more efficient absorption of the drug by the body.
Cyclodextrins (“CD's”) are well-known and are the subject of many reviews. See for example, J. Szejtli, Cyclodextrins and their Inclusion Complexes Budapest:Akademiai Kiado (1982); Loftsson, T., Pharm. Technol. Eur. 1999, 11(10), 2032 and J. S. Pagington, Chemistry in Britain, 1987, 5, 455-458. They consist of glucose units linked in a ring configuration, and more specifically, they are cyclic oligosaccharides composed of α-(1,4)-linked D-glucopyranosyl units. The cyclodextrin molecules have essentially a toroidal or donut shape, with an interior lipophilic cavity and a hydrophobic exterior. The most common cyclodextrins are the naturally occurring α-, β-, and γ- forms, which consist of 6, 7 and 8 glucopyranose units respectively, with the respective cavities having a diameter of 5.7 Å, 7.8 Å, and 9.5 Å. Inclusion complexes are formed when a guest molecule fits partially or entirely within the lipophilic cavity of the cyclodextrin. The driving force for complex formation is the displacement of water molecules by the more hydrophobic guest molecule. The degree and stability of complexation depends on how well the guest molecule, or portions of it, fit within the cavity of the cyclodextrin. The exterior of the cyclodextrin molecule is hydrophilic, which can enhance the aqueous solubility of the complex, and thereby the solubility of the guest molecule.
Cyclodextrin compositions have found some application in the pharmaceutical industry. See Uekama, K, et al., CRC Critical Reviews in therapeutic Drug Carrier Systems, 1987, 3(1), 1-40; Duchene, D, et al., Drug Dev. Ind. Pharm., 1986, 12(11-13) 2193-2215. For example, compositions of Droloxifene in various cyclodextrins are described in U.S. Pat. No. 6,077,871. Solubilization of ibuprofen in cyclodextrin solutions have been described in various patents, including U.S. Pat. No. 5,024,997, U.S. Pat. No. 4,727,064 and U.S. Pat. No. 5,866,162. Pirprofen and cyclodextrin compositions were disclosed in U.S. Pat. No. 4,565,807. A solution of cyclodextrin and modafinil has been reported in Rambert, F. A., et al. Neuropsychopharmacology, 1994, 10(3S), Part 2, 169S. It was reported that 1% and 2% aqueous hydroxypropyl-β-cyclodextrin solutions were prepared for intracerebroventricular injection in rats. However, these solutions were relatively dilute, contain a low concentration of modafinil, and were administered by direct injection into the brain, and not by oral means.
While cyclodextrins have pharmaceutical applications and have been used to solubilize or stabilize many compounds, these uses have had more limited applicability to therapeutic agents and there are many compounds for which cyclodextrin complexation is either not possible, or present disadvantages which render them unsuitable for pharmaceutical use. See J. Szejtli, Pharmaceutical Technology, 1991, 24-38; and U.S. Pat. No. 5,362,860. In particular, the bioavailability of a drug:cyclodextrin mixture is often unpredictable, and indeed formation of drug:cyclodextrin complexes often result in decreased drug bioavailability. See T. Loftsson, Pharmaceutical Technology, 1999, 12, 40-50; and Uekama, K, et al., CRC Critical Reviews in therapeutic Drug Carrier Systems, 1987, 3(1), 1-40.
It has been found by the present inventors that modafinil compound:cyclodextrin mixtures provide for bioavailable delivery of a modafinil compound. While cyclodextrins can increase solubilization of a drug, there is not necessarily a direct correlation to an increase in bioavailability of the drug, or in particular, to bioavailability through oral administration. The mechanisms for drug absorption in these systems are more complicated than a simple correlation to the solubilization profile, as evidenced by the fact that formation of drug-β-cyclodextrin complexes often result in decreased drug bioavailability. The complex itself cannot penetrate a membrane barrier, thus the drug must dissociate from the complex prior to crossing a barrier. The dissociation of the drug is reflected in the stability constant of the drug:complex equilibrium. A stability constant that generally leads to complex formation may also lead to over-lability and premature drug release, while very stable complexes can result in retarded or incomplete release of the drug. Furthermore, a high cyclodextrin concentration or the presence of excipients may additionally hinder complex dissociation, and therefore the absorption of the drug.
The present invention provides for complexes of a modafinil compound and a cyclodextrin particularly inclusion complexes, which provide for enhanced aqueous solubility of the modafinil compound at pharmaceutically useful concentrations, and offer enhanced pharmacological properties. It has been found that such complexes can provide bioavailability of the modafinil compound, in particular, oral bioavailability, as well as effectively taste-mask the modafinil compound thereby providing palatable liquid compositions.